Pulmonary Health Hub

Three large cohort studies examining health issues in World Trade Center rescuers paint a mixed picture, with disturbingly high rates of physical and mental disorders but a paradoxically low all-cause mortality rate thus far, compared with the general New York City population.

More than 50,000 people participated in rescue and recovery work following the 2001 attacks on the World Trade Center a decade ago. A cohort study involving 27,449 of those people who are enrolled in the federally funded WTC Screening, Monitoring, and Treatment Program showed a 9-year cumulative incidence of 28% for asthma, 42% for sinusitis, 39% for gastroesophageal reflux disease (GERD), and 42% for spirometric abnormalities.

Among nonpolice enrollees, the cumulative incidence of depression was 28%, post-traumatic stress disorder (PTSD) 32%, and panic disorder 21%. Police officers had rates of those mental disorders that were only one-third to one-fourth of those rates.

Andrea Booher/FEMA News Photo

Comorbidities were common among the program enrollees, whose median age was 38 years. Overall, 8.6% of rescue and recovery workers had the triad of physician-diagnosed asthma, sinusitis, and GERD. Another 18% had two of the three diseases. Between 40% and 50% of workers with one or more of those medical diseases were also diagnosed with depression, PTSD, and/or panic disorder. Conversely, nearly 70% of workers with one or more of the psychiatric diagnoses also had asthma, GERD, and/or sinusitis.

"Our findings show a substantial burden of persistent physical and mental disorders in rescue and recovery workers who rushed to the site of the WTC and labored there for weeks and months 10 years ago. Many of these individuals now suffer from multiple health problems," concluded Dr. Juan P. Wisnivesky, of the Mount Sinai School of Medicine, New York, and his associates (Lancet 2011;378:888-97).

Mortality Lower Than Expected. Also appearing in the Lancet’s special 9/11 issue was a study demonstrating that all-cause mortality during 2003-2009 in 13,337 rescue and recovery workers was 55% lower than expected, based upon comparison to a demographically similar New York City general population. Mortality in 28,593 bystanders – nonparticipants in the rescue and recovery work who lived or worked in lower Manhattan – was 39% lower than expected. Both reductions were significant.

Among rescue and recovery workers, higher levels of exposure to toxic dust and other WTC-related hazards were not significantly associated with greater all-cause mortality, said Dr. Hannah T. Jordan, of the New York City Department of Health and Mental Hygiene, and her associates (Lancet 2011;378:879-87).

The investigators observed that the reduced mortality in the WTC-exposed population could be explained by a combination of bias due to the healthy worker effect and insufficiently long follow-up to date. Continued monitoring of all-cause and disease-specific mortality is a must, they added.

Cancer Rates and Firefighters. In a third post-9/11 study, cancer rates among 9,853 male firefighters with WTC exposure were 10% greater during the first 7 years of follow-up than in a demographically similar control group obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database.

It’s a modest increase and a relatively short duration of follow-up for cancer outcomes. Moreover, the observed excess in cancers wasn’t limited to specific organ types. In fact, there was an unanticipated 58% lower rate of lung cancer in the WTC-exposed firefighters than in controls, according to Rachel Zeig-Owens, of the department of medicine at Montefiore Medical Center, Bronx, N.Y., and her associates (Lancet 2011;378: 898-905). For all those reasons, the investigators said their findings should be interpreted with caution.

Nonetheless, those data warrant incorporating coverage for cancer in the federally funded medical follow-up of those workers, Dr. James M. Melius said in an interview.

"I do think that the increase in cancer is real. I think that this study, along with what we know about exposures at the WTC – high exposures to multiple carcinogens in a population with an already high disease burden – helps to make the case that cancer should be added to the list," said Dr. Melius of the New York State Laborers’ Health Fund.

"This needs to be viewed in the context that the government should have done more to protect these workers and didn’t, that making them wait 20 or 30 years until definitive studies are done is unfair, and that delay leaves them vulnerable to the economic and personal difficulties from high medical costs – even with insurance – that people in our country often experience," Dr. Melius added.

The studies were variously funded by the Centers for Disease Control and Prevention, the New York City Department of Health and Mental Hygiene, and the National Institute for Occupational Safety and Health. Dr. Wisnivesky is member of the research board of EHE International. All of the other investigators in the three studies reported having no financial conflicts.

Three large cohort studies examining health issues in World Trade Center rescuers paint a mixed picture, with disturbingly high rates of physical and mental disorders but a paradoxically low all-cause mortality rate thus far, compared with the general New York City population.

More than 50,000 people participated in rescue and recovery work following the 2001 attacks on the World Trade Center a decade ago. A cohort study involving 27,449 of those people who are enrolled in the federally funded WTC Screening, Monitoring, and Treatment Program showed a 9-year cumulative incidence of 28% for asthma, 42% for sinusitis, 39% for gastroesophageal reflux disease (GERD), and 42% for spirometric abnormalities.

Among nonpolice enrollees, the cumulative incidence of depression was 28%, post-traumatic stress disorder (PTSD) 32%, and panic disorder 21%. Police officers had rates of those mental disorders that were only one-third to one-fourth of those rates.

Andrea Booher/FEMA News Photo

Comorbidities were common among the program enrollees, whose median age was 38 years. Overall, 8.6% of rescue and recovery workers had the triad of physician-diagnosed asthma, sinusitis, and GERD. Another 18% had two of the three diseases. Between 40% and 50% of workers with one or more of those medical diseases were also diagnosed with depression, PTSD, and/or panic disorder. Conversely, nearly 70% of workers with one or more of the psychiatric diagnoses also had asthma, GERD, and/or sinusitis.

"Our findings show a substantial burden of persistent physical and mental disorders in rescue and recovery workers who rushed to the site of the WTC and labored there for weeks and months 10 years ago. Many of these individuals now suffer from multiple health problems," concluded Dr. Juan P. Wisnivesky, of the Mount Sinai School of Medicine, New York, and his associates (Lancet 2011;378:888-97).

Mortality Lower Than Expected. Also appearing in the Lancet’s special 9/11 issue was a study demonstrating that all-cause mortality during 2003-2009 in 13,337 rescue and recovery workers was 55% lower than expected, based upon comparison to a demographically similar New York City general population. Mortality in 28,593 bystanders – nonparticipants in the rescue and recovery work who lived or worked in lower Manhattan – was 39% lower than expected. Both reductions were significant.

Among rescue and recovery workers, higher levels of exposure to toxic dust and other WTC-related hazards were not significantly associated with greater all-cause mortality, said Dr. Hannah T. Jordan, of the New York City Department of Health and Mental Hygiene, and her associates (Lancet 2011;378:879-87).

The investigators observed that the reduced mortality in the WTC-exposed population could be explained by a combination of bias due to the healthy worker effect and insufficiently long follow-up to date. Continued monitoring of all-cause and disease-specific mortality is a must, they added.

Cancer Rates and Firefighters. In a third post-9/11 study, cancer rates among 9,853 male firefighters with WTC exposure were 10% greater during the first 7 years of follow-up than in a demographically similar control group obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database.

It’s a modest increase and a relatively short duration of follow-up for cancer outcomes. Moreover, the observed excess in cancers wasn’t limited to specific organ types. In fact, there was an unanticipated 58% lower rate of lung cancer in the WTC-exposed firefighters than in controls, according to Rachel Zeig-Owens, of the department of medicine at Montefiore Medical Center, Bronx, N.Y., and her associates (Lancet 2011;378: 898-905). For all those reasons, the investigators said their findings should be interpreted with caution.

Nonetheless, those data warrant incorporating coverage for cancer in the federally funded medical follow-up of those workers, Dr. James M. Melius said in an interview.

"I do think that the increase in cancer is real. I think that this study, along with what we know about exposures at the WTC – high exposures to multiple carcinogens in a population with an already high disease burden – helps to make the case that cancer should be added to the list," said Dr. Melius of the New York State Laborers’ Health Fund.

"This needs to be viewed in the context that the government should have done more to protect these workers and didn’t, that making them wait 20 or 30 years until definitive studies are done is unfair, and that delay leaves them vulnerable to the economic and personal difficulties from high medical costs – even with insurance – that people in our country often experience," Dr. Melius added.

The studies were variously funded by the Centers for Disease Control and Prevention, the New York City Department of Health and Mental Hygiene, and the National Institute for Occupational Safety and Health. Dr. Wisnivesky is member of the research board of EHE International. All of the other investigators in the three studies reported having no financial conflicts.

Three large cohort studies examining health issues in World Trade Center rescuers paint a mixed picture, with disturbingly high rates of physical and mental disorders but a paradoxically low all-cause mortality rate thus far, compared with the general New York City population.

More than 50,000 people participated in rescue and recovery work following the 2001 attacks on the World Trade Center a decade ago. A cohort study involving 27,449 of those people who are enrolled in the federally funded WTC Screening, Monitoring, and Treatment Program showed a 9-year cumulative incidence of 28% for asthma, 42% for sinusitis, 39% for gastroesophageal reflux disease (GERD), and 42% for spirometric abnormalities.

Among nonpolice enrollees, the cumulative incidence of depression was 28%, post-traumatic stress disorder (PTSD) 32%, and panic disorder 21%. Police officers had rates of those mental disorders that were only one-third to one-fourth of those rates.

Andrea Booher/FEMA News Photo

Comorbidities were common among the program enrollees, whose median age was 38 years. Overall, 8.6% of rescue and recovery workers had the triad of physician-diagnosed asthma, sinusitis, and GERD. Another 18% had two of the three diseases. Between 40% and 50% of workers with one or more of those medical diseases were also diagnosed with depression, PTSD, and/or panic disorder. Conversely, nearly 70% of workers with one or more of the psychiatric diagnoses also had asthma, GERD, and/or sinusitis.

"Our findings show a substantial burden of persistent physical and mental disorders in rescue and recovery workers who rushed to the site of the WTC and labored there for weeks and months 10 years ago. Many of these individuals now suffer from multiple health problems," concluded Dr. Juan P. Wisnivesky, of the Mount Sinai School of Medicine, New York, and his associates (Lancet 2011;378:888-97).

Mortality Lower Than Expected. Also appearing in the Lancet’s special 9/11 issue was a study demonstrating that all-cause mortality during 2003-2009 in 13,337 rescue and recovery workers was 55% lower than expected, based upon comparison to a demographically similar New York City general population. Mortality in 28,593 bystanders – nonparticipants in the rescue and recovery work who lived or worked in lower Manhattan – was 39% lower than expected. Both reductions were significant.

Among rescue and recovery workers, higher levels of exposure to toxic dust and other WTC-related hazards were not significantly associated with greater all-cause mortality, said Dr. Hannah T. Jordan, of the New York City Department of Health and Mental Hygiene, and her associates (Lancet 2011;378:879-87).

The investigators observed that the reduced mortality in the WTC-exposed population could be explained by a combination of bias due to the healthy worker effect and insufficiently long follow-up to date. Continued monitoring of all-cause and disease-specific mortality is a must, they added.

Cancer Rates and Firefighters. In a third post-9/11 study, cancer rates among 9,853 male firefighters with WTC exposure were 10% greater during the first 7 years of follow-up than in a demographically similar control group obtained from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database.

It’s a modest increase and a relatively short duration of follow-up for cancer outcomes. Moreover, the observed excess in cancers wasn’t limited to specific organ types. In fact, there was an unanticipated 58% lower rate of lung cancer in the WTC-exposed firefighters than in controls, according to Rachel Zeig-Owens, of the department of medicine at Montefiore Medical Center, Bronx, N.Y., and her associates (Lancet 2011;378: 898-905). For all those reasons, the investigators said their findings should be interpreted with caution.

Nonetheless, those data warrant incorporating coverage for cancer in the federally funded medical follow-up of those workers, Dr. James M. Melius said in an interview.

"I do think that the increase in cancer is real. I think that this study, along with what we know about exposures at the WTC – high exposures to multiple carcinogens in a population with an already high disease burden – helps to make the case that cancer should be added to the list," said Dr. Melius of the New York State Laborers’ Health Fund.

"This needs to be viewed in the context that the government should have done more to protect these workers and didn’t, that making them wait 20 or 30 years until definitive studies are done is unfair, and that delay leaves them vulnerable to the economic and personal difficulties from high medical costs – even with insurance – that people in our country often experience," Dr. Melius added.

The studies were variously funded by the Centers for Disease Control and Prevention, the New York City Department of Health and Mental Hygiene, and the National Institute for Occupational Safety and Health. Dr. Wisnivesky is member of the research board of EHE International. All of the other investigators in the three studies reported having no financial conflicts.

“Looking Beyond the D-dimer” (J Fam Pract. 2011;60:400-403) left me quite confused. The authors described a patient for whom the Wells criteria and a D-dimer were negative for pulmonary embolism (PE) initially but who did, in fact, have a PE. They point out “a key problem with the Wells criteria” and show that the D-dimer was inaccurate, at least relatively early on. Yet they conclude that physicians should use the Wells criteria to evaluate patients and should not work up a patient with a negative D-dimer—which was less than reliable in the case they described.

If, after all of our training and experience as physicians, we are being taught to rely on algorithms and moderately and/or inconsistently reliable tests, we can all retire and let our computers do our jobs. Although I am concerned that much of modern medicine is dictated by health insurers or driven by fear of malpractice claims, we should not exclude clinical judgment and professional acumen. Nor should we read and live by articles that offer contradictory advice.

Doctors, you can’t have it both ways.

Barry Marged, DO, MA
Alliance, Ohio

The authors respond

My colleague and I read your comments with interest. We believe that our case study provides an important message: Utilize evidence-based algorithms that exist in the literature to the best of your ability, but never lose sight of your clinical instincts. These “resources” are complementary, not mutually exclusive.

Good communication with patients affords us the opportunity to stay involved with the evolution of their clinical status and always be ready to reassess. In our case presentation, the Wells criteria allowed us to incorporate the algorithmic thinking into our clinical judgment, but not to replace it. The patient’s ongoing symptoms required a reevaluation, and the Wells criteria proved their worth the second time around. No harm was done to the patient as the PE turned out to be distal and small.

In the end, no clinical algorithm can deliver a guaranteed outcome. In this era of rigorous scrutiny, evidence-based medicine, and cost-effective care, criteria such as the Wells are particularly important. Avoiding unnecessary CT angiography while maintaining close contact with a patient, or assuring immediate follow-up (in the case of an emergency department evaluation) saves valuable resources that can then be deployed elsewhere. Thoughtful rigor, combined with open-mindedness and trust in our clinical instincts, is the way to deliver value-driven, high-quality care.

H. Andrew Selinger, MD
Bristol, Conn

“Looking Beyond the D-dimer” (J Fam Pract. 2011;60:400-403) left me quite confused. The authors described a patient for whom the Wells criteria and a D-dimer were negative for pulmonary embolism (PE) initially but who did, in fact, have a PE. They point out “a key problem with the Wells criteria” and show that the D-dimer was inaccurate, at least relatively early on. Yet they conclude that physicians should use the Wells criteria to evaluate patients and should not work up a patient with a negative D-dimer—which was less than reliable in the case they described.

If, after all of our training and experience as physicians, we are being taught to rely on algorithms and moderately and/or inconsistently reliable tests, we can all retire and let our computers do our jobs. Although I am concerned that much of modern medicine is dictated by health insurers or driven by fear of malpractice claims, we should not exclude clinical judgment and professional acumen. Nor should we read and live by articles that offer contradictory advice.

Doctors, you can’t have it both ways.

Barry Marged, DO, MA
Alliance, Ohio

The authors respond

My colleague and I read your comments with interest. We believe that our case study provides an important message: Utilize evidence-based algorithms that exist in the literature to the best of your ability, but never lose sight of your clinical instincts. These “resources” are complementary, not mutually exclusive.

Good communication with patients affords us the opportunity to stay involved with the evolution of their clinical status and always be ready to reassess. In our case presentation, the Wells criteria allowed us to incorporate the algorithmic thinking into our clinical judgment, but not to replace it. The patient’s ongoing symptoms required a reevaluation, and the Wells criteria proved their worth the second time around. No harm was done to the patient as the PE turned out to be distal and small.

In the end, no clinical algorithm can deliver a guaranteed outcome. In this era of rigorous scrutiny, evidence-based medicine, and cost-effective care, criteria such as the Wells are particularly important. Avoiding unnecessary CT angiography while maintaining close contact with a patient, or assuring immediate follow-up (in the case of an emergency department evaluation) saves valuable resources that can then be deployed elsewhere. Thoughtful rigor, combined with open-mindedness and trust in our clinical instincts, is the way to deliver value-driven, high-quality care.

H. Andrew Selinger, MD
Bristol, Conn

“Looking Beyond the D-dimer” (J Fam Pract. 2011;60:400-403) left me quite confused. The authors described a patient for whom the Wells criteria and a D-dimer were negative for pulmonary embolism (PE) initially but who did, in fact, have a PE. They point out “a key problem with the Wells criteria” and show that the D-dimer was inaccurate, at least relatively early on. Yet they conclude that physicians should use the Wells criteria to evaluate patients and should not work up a patient with a negative D-dimer—which was less than reliable in the case they described.

If, after all of our training and experience as physicians, we are being taught to rely on algorithms and moderately and/or inconsistently reliable tests, we can all retire and let our computers do our jobs. Although I am concerned that much of modern medicine is dictated by health insurers or driven by fear of malpractice claims, we should not exclude clinical judgment and professional acumen. Nor should we read and live by articles that offer contradictory advice.

Doctors, you can’t have it both ways.

Barry Marged, DO, MA
Alliance, Ohio

The authors respond

My colleague and I read your comments with interest. We believe that our case study provides an important message: Utilize evidence-based algorithms that exist in the literature to the best of your ability, but never lose sight of your clinical instincts. These “resources” are complementary, not mutually exclusive.

Good communication with patients affords us the opportunity to stay involved with the evolution of their clinical status and always be ready to reassess. In our case presentation, the Wells criteria allowed us to incorporate the algorithmic thinking into our clinical judgment, but not to replace it. The patient’s ongoing symptoms required a reevaluation, and the Wells criteria proved their worth the second time around. No harm was done to the patient as the PE turned out to be distal and small.

In the end, no clinical algorithm can deliver a guaranteed outcome. In this era of rigorous scrutiny, evidence-based medicine, and cost-effective care, criteria such as the Wells are particularly important. Avoiding unnecessary CT angiography while maintaining close contact with a patient, or assuring immediate follow-up (in the case of an emergency department evaluation) saves valuable resources that can then be deployed elsewhere. Thoughtful rigor, combined with open-mindedness and trust in our clinical instincts, is the way to deliver value-driven, high-quality care.

H. Andrew Selinger, MD
Bristol, Conn

The Food and Drug Administration on Aug. 25 approved icatibant for the treatment of acute attacks of hereditary angioedema in adults aged 18 years and older.

Icatibant is administered subcutaneously at the onset of attack symptoms, which can include rapid swelling of different body parts – usually the face, GI tract, extremities, or genitals – with airway swelling that can increase the risk of suffocation.

"Because it can be self-administered through an injection in the abdominal area, patients can treat themselves upon recognition of an HAE attack," Dr. Curtis Rosebraugh, director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing the approval.

Icatibant, a selective bradykinin B2 receptor antagonist, inhibits the effects of bradykinin, thought to be the cause of HAE symptoms, according to Shire Human Genetic Therapies, which will market the drug as Firazyr. One syringe costs $6,800 (average wholesale price), according to a company spokesperson. The company has a program to help eligible patients help pay for copays as well as a program to help uninsured patients or those patients whose insurance does not cover the treatment.

This is the third drug approved by the FDA to treat attacks of HAE, a rare genetic disorder that affects fewer than 30,000 people in the United States: a C1 esterase inhibitor (Berinert) was approved in October 2009, to treat facial and abdominal attacks of HAE, and ecallantide (Kalbitor) was approved in December 2009 to treat acute attacks of HAE in patients aged 16 years and older.

In three controlled studies, with open-label extension periods, 225 patients were treated with 1,076 icatibant injections. Those treated with icatibant started to experience relief of symptoms in a median of 2 hours after the injection, compared with almost 20 hours among those who received a placebo injection. The most common side effects associated with icatibant were injection site reactions, fever, elevated liver enzymes, dizziness, and rash, according to the FDA.

Icatibant, which is launching in the United States on Aug. 26, is now approved in 38 countries, including those in the European Union, according to Shire.

The Food and Drug Administration on Aug. 25 approved icatibant for the treatment of acute attacks of hereditary angioedema in adults aged 18 years and older.

Icatibant is administered subcutaneously at the onset of attack symptoms, which can include rapid swelling of different body parts – usually the face, GI tract, extremities, or genitals – with airway swelling that can increase the risk of suffocation.

"Because it can be self-administered through an injection in the abdominal area, patients can treat themselves upon recognition of an HAE attack," Dr. Curtis Rosebraugh, director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing the approval.

Icatibant, a selective bradykinin B2 receptor antagonist, inhibits the effects of bradykinin, thought to be the cause of HAE symptoms, according to Shire Human Genetic Therapies, which will market the drug as Firazyr. One syringe costs $6,800 (average wholesale price), according to a company spokesperson. The company has a program to help eligible patients help pay for copays as well as a program to help uninsured patients or those patients whose insurance does not cover the treatment.

This is the third drug approved by the FDA to treat attacks of HAE, a rare genetic disorder that affects fewer than 30,000 people in the United States: a C1 esterase inhibitor (Berinert) was approved in October 2009, to treat facial and abdominal attacks of HAE, and ecallantide (Kalbitor) was approved in December 2009 to treat acute attacks of HAE in patients aged 16 years and older.

In three controlled studies, with open-label extension periods, 225 patients were treated with 1,076 icatibant injections. Those treated with icatibant started to experience relief of symptoms in a median of 2 hours after the injection, compared with almost 20 hours among those who received a placebo injection. The most common side effects associated with icatibant were injection site reactions, fever, elevated liver enzymes, dizziness, and rash, according to the FDA.

Icatibant, which is launching in the United States on Aug. 26, is now approved in 38 countries, including those in the European Union, according to Shire.

The Food and Drug Administration on Aug. 25 approved icatibant for the treatment of acute attacks of hereditary angioedema in adults aged 18 years and older.

Icatibant is administered subcutaneously at the onset of attack symptoms, which can include rapid swelling of different body parts – usually the face, GI tract, extremities, or genitals – with airway swelling that can increase the risk of suffocation.

"Because it can be self-administered through an injection in the abdominal area, patients can treat themselves upon recognition of an HAE attack," Dr. Curtis Rosebraugh, director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing the approval.

Icatibant, a selective bradykinin B2 receptor antagonist, inhibits the effects of bradykinin, thought to be the cause of HAE symptoms, according to Shire Human Genetic Therapies, which will market the drug as Firazyr. One syringe costs $6,800 (average wholesale price), according to a company spokesperson. The company has a program to help eligible patients help pay for copays as well as a program to help uninsured patients or those patients whose insurance does not cover the treatment.

This is the third drug approved by the FDA to treat attacks of HAE, a rare genetic disorder that affects fewer than 30,000 people in the United States: a C1 esterase inhibitor (Berinert) was approved in October 2009, to treat facial and abdominal attacks of HAE, and ecallantide (Kalbitor) was approved in December 2009 to treat acute attacks of HAE in patients aged 16 years and older.

In three controlled studies, with open-label extension periods, 225 patients were treated with 1,076 icatibant injections. Those treated with icatibant started to experience relief of symptoms in a median of 2 hours after the injection, compared with almost 20 hours among those who received a placebo injection. The most common side effects associated with icatibant were injection site reactions, fever, elevated liver enzymes, dizziness, and rash, according to the FDA.

Icatibant, which is launching in the United States on Aug. 26, is now approved in 38 countries, including those in the European Union, according to Shire.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Daily azithromycin prevented acute exacerbations of chronic obstructive pulmonary disease when it was added to usual treatment in a 1-year study, thus improving patients’ quality of life, according to a report in the Aug. 25 issue of the New England Journal of Medicine.

The drug also cut the colonization of certain respiratory pathogens. On the downside, it increased colonization with macrolide-resistant organisms and induced hearing decrements in approximately 5% of patients, said Dr. Richard K. Albert, professor of medicine at the University of Colorado at Denver and chief of medicine at Denver Health, and his associates.

"Given the deleterious effects of acute exacerbations of COPD with respect to the risk of death, quality of life, loss of lung function, and cost of care, adding azithromycin to the treatment regimen [of at-risk patients] is a valuable option," they noted.

However, QTc prolongation is a contraindication to the drug, and patients who are at risk for the cardiac disorder should be monitored if they are given azithromycin. Hearing also should be monitored in all patients. "In addition, it should be recognized that the long-term effects of this treatment on microbial resistance in the community are not known," the investigators said.

Macrolide antibiotics like azithromycin have immunomodulatory and anti-inflammatory properties in addition to their antibacterial action. Several small studies have examined their use in preventing acute exacerbations of COPD, with conflicting results. "Accordingly, we conducted a large, randomized trial to test the hypothesis that azithromycin decreases the frequency of acute exacerbations of COPD when added to the usual care of these patients," said Dr. Albert and his colleagues in the COPD Clinical Research Network.

The prospective study involved 1,142 patients aged 40 years and older who were at risk for acute exacerbations and were randomly assigned to receive either 250 mg of oral azithromycin (570 subjects) or an identical-looking placebo (572 subjects) once daily for 1 year. All were already using inhaled glucocorticoids, long-acting beta-agonists, muscarinic antagonists, and/or continuous supplemental oxygen.

These subjects were followed at 17 sites associated with academic health centers across the United States.

The primary outcome measure – time to the first acute exacerbation of COPD – was significantly increased in the patients taking azithromycin (266 days), compared with those taking placebo (174 days). The hazard ratio of having an acute exacerbation per patient-year was 0.73 in the azithromycin group, compared with the placebo group.

These differences remained significant after the data were adjusted to account for differences between the two groups in sex, forced expiratory volume in 1 second (FEV₁), age, and smoking status, the researchers said (N. Engl. J. Med. 2011;365:689-98).

There were 1,641 acute exacerbations of COPD during the study, and the number was significantly lower in the active-treatment group (741) than in the placebo group (900). "The number needed to treat to prevent one acute exacerbation of COPD was 2.86," they said.

More patients in the azithromycin group than in the placebo group showed significant improvements in quality of life scores.

There were no significant differences between the two groups in the frequency of serious adverse events or of adverse events that prompted discontinuation of treatment. Audiograms showed hearing decrements in 25% of patients taking azithromycin, compared with 20% of those taking placebo.

Among study subjects whose nasopharyngeal swabs showed colonization with respiratory pathogens at baseline, the later prevalence of organisms that were resistant to macrolides was comparable whether they took azithromycin or placebo. In contrast, among subjects who became colonized during the study, the rate of macrolide resistance was twice as high in those taking azithromycin (81%) as in those taking placebo (41%).

"We cannot comment on the safety profile of azithromycin when it is taken for longer than 1 year, and we have no information pertaining to potential effects of long-term macrolide administration on bacterial resistance patterns in the community," Dr. Albert and his associates noted.

They added that they chose the 250-mg dose of azithromycin to minimize the chance of insufficient dosing, and chose daily rather than less-frequent administration to maximize adherence. "It is possible that lower doses or less frequent administration could have produced similar results," Dr. Albert and his colleagues said.

This study was funded by the National Heart, Lung, and Blood Institute and the COPD Clinical Research Network. Dr. Albert reported ties to Gilead Sciences, the Bruce Fagel Law Firm, Elsevier, and Denver Health, and his associates reported ties to numerous industry sources including Pfizer, the marketer of Zithromax in the United States.

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.

Nebulized hypertonic saline is an emerging therapy for this indication.

Viral bronchiolitis is the most common diagnosis at hospitalization for infants younger than 1 year of age.

It results in approximately 150,000 hospitalizations each year at a cost of more than $500 million, according to a study published in 2006 (Pediatrics 2006;118:2418-23). Yet so far, nothing we give our patients really works.

Nebulized hypertonic saline is garnering enthusiasm because there is a consistent set of papers and a theory of physiology supporting its efficacy in the treatment of acute viral bronchiolitis.

The very first hypertonic saline study came from a group of Israeli pulmonologists who reported an improvement in symptoms and respiratory scores on day 2 of inhaled nebulized 3% saline solution plus 5-mg terbutaline in 33 outpatient infants with viral bronchiolitis, compared with 32 control infants who received 0.9% saline plus 5 mg terbutaline (Chest 2002;122:2015-20).

The findings led the researchers to conduct a second randomized, controlled study, this time combining 3% hypertonic saline with 1.5-mg epinephrine three times a day until discharge among 27 hospitalized infants. Clinical severity scores improved significantly after 24 hours of therapy and almost a full day was shaved off the length of stay (LOS), compared with normal saline plus epinephrine in 25 infants (Chest 2003;123:481-7).

The group came back a year later with a second year of follow-up in 41 inpatients and essentially replicated their findings (Isr. Med. Assoc. J. 2006;8:169-73).

The study that caught most hospitalists’ eyes, however, was a multicenter, double-blind Canadian trial that left the concomitant use of beta-agonists up to the discretion of the physicians who treated 96 infants hospitalized with moderately severe viral bronchiolitis (J. Pediatr. 2007;151:266-70). Even though 30% of the infants did not receive beta-agonists, the use of hypertonic saline resulted in a clinically relevant 26% reduction in LOS (from 3.5 days to 2.6 days) with normal saline. Symptoms diverged the longer the infants were treated.

Short-term improvement was not really expected, based on the theory that hypertonic saline works by rehydrating the airway surface liquid (ASL), as well as inducing cough and improving sputum mobility. The Israelis theorized that mucociliary failure, such as occurs in cystic fibrosis, also occurs in severe bronchiolitis because of dehydration of the ASL, the thin layer of fluid that covers the luminal surface of the airway.

In vitro, hypertonic saline increases airway surface thickness, decreases epithelial edema, and improves mucus rheology and transport rates. In vivo, it increases mucociliary transport in healthy subjects.

Thus, it makes sense that short-term studies have found no difference in outcomes, and that studies demonstrating positive effects on LOS and respiratory scores do so only after 24 hours of therapy. Fluid shifts take time, and cilia can only do so much.

Chinese investigators have reported similar positive outcomes, including a reduction in LOS from 7.4 to 6 days with hypertonic saline plus salbutamol in hospitalized infants (Pediatr. Int. 2010;52:199-202). Moreover, these findings were replicated in a second study, this time using nebulized 3% hypertonic saline without concomitant bronchodilators (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

We’ve never seen this level of consistently positive results in the data on bronchiolitis treatment in the past, and it’s exciting – particularly as we have so little in our therapeutic armamentarium. It’s also very interesting to have a theory of mechanism of action that meshes with the known pathology in bronchiolitis. After years of repeatedly studying beta-agonists, even though we knew that airway smooth muscle reactivity was not the major pathology, it is refreshing to see a different approach emerging.

Dr. Ralston is chief of inpatient pediatrics at the University of Texas Health Science Center in San Antonio. She said she had no relevant financial disclosures.

It is too early to say if hypertonic saline is an appropriate therapy.

Much of the evidence supporting the use of nebulized hypertonic saline for acute bronchiolitis rests on changes in respiratory scores that are not likely to have clinical relevance. The true test is whether hypertonic saline can really reduce length of stay (LOS), the hard outcome that hospitalists and parents care about. That question remains unanswered.

No fewer than five short-term emergency department (ED) studies have failed to find a difference in outcomes between nebulized hypertonic saline and normal saline. One of those trials was by the same group of Canadian researchers that helped put nebulized hypertonic saline on the radar of many hospitalists and pediatricians (J. Pediatr. 2007;151:266-70).

When the Canadians studied hypertonic saline in the ED setting, there were no significant differences in hospital admission rates or respiratory scores after three consecutive 4-mL doses of nebulized 3% hypertonic saline in children younger than age 2 years who presented to the ED with moderately severe bronchiolitis (CJEM 2010;12:477-84).

In addition, no large randomized trials from the United States have been conducted using our criteria for hospitalization. A recent Chinese study demonstrated a reduction in LOS with the use of hypertonic saline plus salbutamol in 93 infants hospitalized with mild to moderate bronchiolitis (Pediatr. Int. 2010;52:199-202). The reduction, however, was from 7.4 days to 6.0 days – an LOS that was more than double the U.S. average LOS of 2.5 days.

The same researchers evaluated nebulized 3% hypertonic saline without bronchodilators, and reported a similar reduction in LOS from an average of 6.4 days with normal saline to a full 4.8 days with hypertonic saline (Clin. Microbiol. Infect. 2010 July 15 [Epub ahead of print]).

Dr. Susan Wu and her colleagues at Childrens Hospital Los Angeles presented data, however, at the recent Pediatric Hospital Medicine 2011 meeting that contradicts these findings. Although the preliminary analysis includes subjects from only the first 2 years of the study and was not fully powered for the LOS outcome, hypertonic saline was no better than normal saline for respiratory distress, and actually resulted in a longer LOS of 3.46 days compared with 2.74 days with normal saline (Pediatric Hospital Medicine 2011;1 [poster session B, July 29] abstract 4).

One also has to question whether the cost of respiratory therapy labor to provide such a potentially ineffective therapy can be justified in the current health care environment, when hypertonic saline hasn’t been established as being superior to the guideline recommendation of supportive care only.

Some may argue that the cost of hypertonic saline is free, but a quick back-of-the-envelope calculation would suggest otherwise. If you practice in a 90-bed hospital, see 500 bronchiolitis patients per year, and have a 3-day LOS using hypertonic saline every 4 hours, that works out to 12,000 nebulizations and 400 hours of respiratory time, which ends up costing $300,000 per year. At that price tag, one could hire a full-time employee for your hospitalist team.

Many administrations may also insist that hypertonic saline be given with albuterol, which one could argue may in some cases actually extend LOS because of the potential for patients to desaturate.

Finally, if you’re a fee-for-service hospital, there’s a financial disincentive for your administration to spend $300,000 for a therapy that could actually reduce profits by shortening LOS. Hospitals adopt measures that shorten LOS, but few would be willing to implement such a strategy until a large, randomized, controlled trial conducted in the United States has proved that hypertonic saline, likely without albuterol, is both clinically and cost effective.

Dr. Alverson is director of pediatric hospital medicine at Hasbro Children’s Hospital in Providence, R.I. He said that he had no relevant financial disclosures.

This column, Point/Counterpoint, regularly appears in Pediatric News, an Elsevier publication.

COLORADO SPRINGS – A disproportionate share of donor lungs goes to local, low-priority recipients, according to an analysis of data from the United Network for Organ Sharing.

The current lung allocation system results in a high proportion of donor organs being distributed to low-priority candidates who often receive little survival benefit from their transplant. Meanwhile, higher-priority candidates who might derive more benefit from transplantation continue to die at high rates on the waiting list, Dr. Alexander Iribarne said at the annual meeting of the Western Thoracic Surgical Association.

He presented an argument for the sharing of donor lungs over a broader geographical range in the United States. The analysis involved all 7,171 lung transplants done in the United States between May 2005 and the end of 2010.

May 2005 was chosen as the starting date because that’s when the Lung Allocation Score (LAS) was introduced as a measure for allocating organs on the basis of medical urgency rather than waiting time. An LAS score lower than 50 defines a transplant candidate as low priority, a score of 50-75 is considered intermediate, and an LAS greater than 75 is high priority.

Among the 5,544 transplants that were performed in low-priority recipients, 54% of the donor organs were allocated locally, 17% regionally, and 29% nationally. In contrast, 40% of the 1,016 transplants in recipients with an LAS of 50-75 at the time of surgery were allocated locally, as were 33% of the donor organs used in patients with an LAS greater than 75.

What’s happening is that when an organ becomes available in one of the less-populated local donor service areas, there’s a lower likelihood that a suitable higher-priority candidate will be in place than in a more populous donor service area, said Dr. Iribarne of Columbia University, New York.

As a result, the organ often goes to a local patient with an LAS lower than 50.

The UNOS data showed that in donor service areas having a population of fewer than 6.1 million, nearly 75% of locally allocated donor lungs went to patients with an LAS lower than 50. In local donor service areas with a population in excess of 10.3 million people, a greater percentage of lungs are allocated to higher-priority recipients, according to Dr. Iribarne.

The next step in this research should be to determine whether organ sharing across broader geographical areas results in higher rates of lung allocation to higher-priority candidates and improved survival for those on the waiting list, he added.

Dr. Iribarne declared having no financial conflicts.

COLORADO SPRINGS – A disproportionate share of donor lungs goes to local, low-priority recipients, according to an analysis of data from the United Network for Organ Sharing.

The current lung allocation system results in a high proportion of donor organs being distributed to low-priority candidates who often receive little survival benefit from their transplant. Meanwhile, higher-priority candidates who might derive more benefit from transplantation continue to die at high rates on the waiting list, Dr. Alexander Iribarne said at the annual meeting of the Western Thoracic Surgical Association.

He presented an argument for the sharing of donor lungs over a broader geographical range in the United States. The analysis involved all 7,171 lung transplants done in the United States between May 2005 and the end of 2010.

May 2005 was chosen as the starting date because that’s when the Lung Allocation Score (LAS) was introduced as a measure for allocating organs on the basis of medical urgency rather than waiting time. An LAS score lower than 50 defines a transplant candidate as low priority, a score of 50-75 is considered intermediate, and an LAS greater than 75 is high priority.

Among the 5,544 transplants that were performed in low-priority recipients, 54% of the donor organs were allocated locally, 17% regionally, and 29% nationally. In contrast, 40% of the 1,016 transplants in recipients with an LAS of 50-75 at the time of surgery were allocated locally, as were 33% of the donor organs used in patients with an LAS greater than 75.

What’s happening is that when an organ becomes available in one of the less-populated local donor service areas, there’s a lower likelihood that a suitable higher-priority candidate will be in place than in a more populous donor service area, said Dr. Iribarne of Columbia University, New York.

As a result, the organ often goes to a local patient with an LAS lower than 50.

The UNOS data showed that in donor service areas having a population of fewer than 6.1 million, nearly 75% of locally allocated donor lungs went to patients with an LAS lower than 50. In local donor service areas with a population in excess of 10.3 million people, a greater percentage of lungs are allocated to higher-priority recipients, according to Dr. Iribarne.

The next step in this research should be to determine whether organ sharing across broader geographical areas results in higher rates of lung allocation to higher-priority candidates and improved survival for those on the waiting list, he added.

Dr. Iribarne declared having no financial conflicts.

COLORADO SPRINGS – A disproportionate share of donor lungs goes to local, low-priority recipients, according to an analysis of data from the United Network for Organ Sharing.

The current lung allocation system results in a high proportion of donor organs being distributed to low-priority candidates who often receive little survival benefit from their transplant. Meanwhile, higher-priority candidates who might derive more benefit from transplantation continue to die at high rates on the waiting list, Dr. Alexander Iribarne said at the annual meeting of the Western Thoracic Surgical Association.

He presented an argument for the sharing of donor lungs over a broader geographical range in the United States. The analysis involved all 7,171 lung transplants done in the United States between May 2005 and the end of 2010.

May 2005 was chosen as the starting date because that’s when the Lung Allocation Score (LAS) was introduced as a measure for allocating organs on the basis of medical urgency rather than waiting time. An LAS score lower than 50 defines a transplant candidate as low priority, a score of 50-75 is considered intermediate, and an LAS greater than 75 is high priority.

Among the 5,544 transplants that were performed in low-priority recipients, 54% of the donor organs were allocated locally, 17% regionally, and 29% nationally. In contrast, 40% of the 1,016 transplants in recipients with an LAS of 50-75 at the time of surgery were allocated locally, as were 33% of the donor organs used in patients with an LAS greater than 75.

What’s happening is that when an organ becomes available in one of the less-populated local donor service areas, there’s a lower likelihood that a suitable higher-priority candidate will be in place than in a more populous donor service area, said Dr. Iribarne of Columbia University, New York.

As a result, the organ often goes to a local patient with an LAS lower than 50.

The UNOS data showed that in donor service areas having a population of fewer than 6.1 million, nearly 75% of locally allocated donor lungs went to patients with an LAS lower than 50. In local donor service areas with a population in excess of 10.3 million people, a greater percentage of lungs are allocated to higher-priority recipients, according to Dr. Iribarne.

The next step in this research should be to determine whether organ sharing across broader geographical areas results in higher rates of lung allocation to higher-priority candidates and improved survival for those on the waiting list, he added.

Dr. Iribarne declared having no financial conflicts.

VAIL, COLO. – Results of a landmark study of a far simpler and more convenient treatment regimen for latent tuberculosis infection are expected to transform clinical pediatric practice in relatively short order, Dr. John W. Ogle said.

The Centers for Disease Control and Prevention–sponsored PREVENT TB trial included 8,053 participants with latent TB, of whom nearly 1,000 were children older than age 2 years. Participants were randomized to either the standard treatment regimen of daily self-administered isoniazid for 9 months, or a novel regimen consisting of directly observed therapy with isoniazid (INH) and rifapentine (INN) once-weekly for 3 months. With 33 months of follow-up, the new regimen was as effective in preventing cases of active TB as was the standard regimen. However, the once-weekly therapy had significantly better adherence and fewer side effects, which was not surprising given that it entailed only 12 total doses of medication, compared with 270 doses in the standard regimen.

The soon-to-be-published study was presented earlier this year in Denver at a meeting of the American Thoracic Society. The CDC has called the PREVENT TB findings "one of the most significant advances in TB research in decades." An expert panel has been convened to analyze the data and begin working on new U.S. treatment guidelines.

The shorter-course regimen appeared to be as effective as standard therapy in children as well as in adults. The increased rate of hepatitis and other isoniazid-related side effects that is seen with standard therapy was more striking in adults than in children, but that’s to be expected because adults typically have more toxicities than do children, Dr. Ogle observed at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

"It’s very likely that we’re going to be urged to adopt this INH/INN regimen as routine therapy because it’s so much easier," predicted Dr. Ogle, professor of pediatrics at the University of Colorado at Denver and director of pediatric services at Denver Health Medical Center.

That being said, he urged his pediatric colleagues to remain vigilant as they adopt the anticipated new guidelines.

"When this regimen is broadened to a bigger population, we’ll undoubtedly learn new things. That’s what always happens when you take a moderately or even a big-powered study and adopt it in another population. No one knows the incidence of side effects in the general population. We’ve seen a couple of kids who’ve had rifapentine reactions," Dr. Ogle said.

As an aside, Dr. Ogle noted that he hasn’t prescribed liquid isoniazid in more than 10 years. "I’ve found it to be a reliable way to give a child diarrhea. We’ll crush the tablets instead, even down to a 1-month-old infant," he said.

Dr. Ogle declared having no relevant financial disclosures.

VAIL, COLO. – Results of a landmark study of a far simpler and more convenient treatment regimen for latent tuberculosis infection are expected to transform clinical pediatric practice in relatively short order, Dr. John W. Ogle said.

The Centers for Disease Control and Prevention–sponsored PREVENT TB trial included 8,053 participants with latent TB, of whom nearly 1,000 were children older than age 2 years. Participants were randomized to either the standard treatment regimen of daily self-administered isoniazid for 9 months, or a novel regimen consisting of directly observed therapy with isoniazid (INH) and rifapentine (INN) once-weekly for 3 months. With 33 months of follow-up, the new regimen was as effective in preventing cases of active TB as was the standard regimen. However, the once-weekly therapy had significantly better adherence and fewer side effects, which was not surprising given that it entailed only 12 total doses of medication, compared with 270 doses in the standard regimen.

The soon-to-be-published study was presented earlier this year in Denver at a meeting of the American Thoracic Society. The CDC has called the PREVENT TB findings "one of the most significant advances in TB research in decades." An expert panel has been convened to analyze the data and begin working on new U.S. treatment guidelines.

The shorter-course regimen appeared to be as effective as standard therapy in children as well as in adults. The increased rate of hepatitis and other isoniazid-related side effects that is seen with standard therapy was more striking in adults than in children, but that’s to be expected because adults typically have more toxicities than do children, Dr. Ogle observed at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

"It’s very likely that we’re going to be urged to adopt this INH/INN regimen as routine therapy because it’s so much easier," predicted Dr. Ogle, professor of pediatrics at the University of Colorado at Denver and director of pediatric services at Denver Health Medical Center.

That being said, he urged his pediatric colleagues to remain vigilant as they adopt the anticipated new guidelines.

"When this regimen is broadened to a bigger population, we’ll undoubtedly learn new things. That’s what always happens when you take a moderately or even a big-powered study and adopt it in another population. No one knows the incidence of side effects in the general population. We’ve seen a couple of kids who’ve had rifapentine reactions," Dr. Ogle said.

As an aside, Dr. Ogle noted that he hasn’t prescribed liquid isoniazid in more than 10 years. "I’ve found it to be a reliable way to give a child diarrhea. We’ll crush the tablets instead, even down to a 1-month-old infant," he said.

Dr. Ogle declared having no relevant financial disclosures.

VAIL, COLO. – Results of a landmark study of a far simpler and more convenient treatment regimen for latent tuberculosis infection are expected to transform clinical pediatric practice in relatively short order, Dr. John W. Ogle said.

The Centers for Disease Control and Prevention–sponsored PREVENT TB trial included 8,053 participants with latent TB, of whom nearly 1,000 were children older than age 2 years. Participants were randomized to either the standard treatment regimen of daily self-administered isoniazid for 9 months, or a novel regimen consisting of directly observed therapy with isoniazid (INH) and rifapentine (INN) once-weekly for 3 months. With 33 months of follow-up, the new regimen was as effective in preventing cases of active TB as was the standard regimen. However, the once-weekly therapy had significantly better adherence and fewer side effects, which was not surprising given that it entailed only 12 total doses of medication, compared with 270 doses in the standard regimen.

The soon-to-be-published study was presented earlier this year in Denver at a meeting of the American Thoracic Society. The CDC has called the PREVENT TB findings "one of the most significant advances in TB research in decades." An expert panel has been convened to analyze the data and begin working on new U.S. treatment guidelines.

The shorter-course regimen appeared to be as effective as standard therapy in children as well as in adults. The increased rate of hepatitis and other isoniazid-related side effects that is seen with standard therapy was more striking in adults than in children, but that’s to be expected because adults typically have more toxicities than do children, Dr. Ogle observed at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

"It’s very likely that we’re going to be urged to adopt this INH/INN regimen as routine therapy because it’s so much easier," predicted Dr. Ogle, professor of pediatrics at the University of Colorado at Denver and director of pediatric services at Denver Health Medical Center.

That being said, he urged his pediatric colleagues to remain vigilant as they adopt the anticipated new guidelines.

"When this regimen is broadened to a bigger population, we’ll undoubtedly learn new things. That’s what always happens when you take a moderately or even a big-powered study and adopt it in another population. No one knows the incidence of side effects in the general population. We’ve seen a couple of kids who’ve had rifapentine reactions," Dr. Ogle said.

As an aside, Dr. Ogle noted that he hasn’t prescribed liquid isoniazid in more than 10 years. "I’ve found it to be a reliable way to give a child diarrhea. We’ll crush the tablets instead, even down to a 1-month-old infant," he said.

Dr. Ogle declared having no relevant financial disclosures.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.

These results show that combined intrapleural TPA and DNase therapy improves the drainage of pleural fluid in patients with pleural infection and may improve the natural history of infection, including reduced hospital stays and the need for thoracic surgery.

"This combined treatment may therefore be useful in patients in whom standard medical management has failed and thoracic surgery is not a treatment option," the researchers say. "However, appropriate trials are needed to accurately define the treatment effects. If confirmed in further studies, our results will inform the choice of intrapleural adjuvant therapy for pleural infection and improve the management of this disorder," according to the researchers.

The study was funded by an unrestricted educational grant from Roche UK to the University of Oxford and by grants from the Oxford Biomedical Research Centre Programme, through the United Kingdom National Institute for Health Research) and the United Kingdom Medical Research Council. Dr. Chris W.H. Davies and Dr. John M. Wrightston disclosed receiving lecture fees from ResMed UK and Boehringer Ingelheim UK, respectively.

VANCOUVER, B.C. – The impact of selective serotonin reuptake inhibitors on fetal pulmonary vascular physiology may boil down to genetics, study results suggest.

In a study of 55 pregnant women who were near term, a variety of right pulmonary artery measures (such as flow and impedance) did not differ significantly between fetuses of women who had been taking SSRIs since conception and those of women who had not. There was also no measurable effect of acute exposure to SSRIs.

However, within the SSRI-exposed group only, fetal right pulmonary artery flow was about 40% higher for infants who experienced respiratory distress in the neonatal period than for their counterparts who did not.

"So there is something different about this particular group in terms of the fact that they developed respiratory distress," commented lead investigator Dr. Kenneth Lim. "Maybe they respond to the SSRIs differently; maybe there is a genetic polymorphism that makes them more susceptible."

Regardless, this difference can be tapped to elucidate the effects of in utero exposure, he added. "It just sort of gives us an idea that maybe we need to look at that a little bit more closely in the next phase of our studies, to try to determine whether there is something going on in the pulmonary system of these babies."

Some 4% of pregnant women in British Columbia are taking SSRIs, according to Dr. Lim of the department of obstetrics and gynecology at the University of British Columbia in Vancouver. "In a province our size, that’s about 1,500-2,000 patients a year who are exposed to SSRIs," he noted at the annual meeting of the Society of Obstetricians and Gynaecologists of Canada.

Previous studies have determined that maternal use of this class of drugs has a variety of deleterious effects on the infant, including low birth weight, prematurity, and a type of withdrawal syndrome characterized by irritability and jitteriness.

"But interestingly, there is also a link with respiratory distress, which tends to be more like a TTN [transient tachypnea of the newborn]-type respiratory distress, and also, there have been case reports of primary pulmonary hypertension," he noted.

The pathogenesis of these pulmonary abnormalities is unclear. "We do know that serotonin itself is a very powerful vasoconstrictor, but it has differential effects in different tissues," Dr. Lim explained.

Preclinically, serotonin impairs lung fluid resorption, suggesting that SSRI-exposed infants may be unable to reabsorb lung fluid after birth; one SSRI has been found to increase arterial smooth muscle cell proliferation.

Pregnant women were eligible for the study if their fetus did not have any anomalies, if they were not taking any illicit or prescription drugs (other than SSRIs), and if they did not have any serious medical conditions.

The investigators enrolled two groups. The nonexposed control group consisted of healthy women who were at low risk for complications and who had not taken SSRIs during pregnancy. The exposed group consisted of women with a mood disorder who had been taking SSRIs since the time of conception.

At a gestational age of about 36 weeks, the women underwent a morning ultrasound exam to assess fetal pulmonary vasculature. Those taking an SSRI then took their medication for the day. In the afternoon, all women had a second ultrasound.

This approach allowed assessment of the effects of both chronic SSRI exposure (by comparing exposed and nonexposed groups) and acute SSRI exposure (by comparing morning and afternoon measurements in the exposed group), Dr. Lim explained.

Results were based on 23 women taking SSRIs (predominantly fluoxetine) and 32 control women. They were 33 years old, on average. Only a single woman in each group smoked during pregnancy. Those in the SSRI group had higher scores for depression.

At delivery, the gestational age was significantly younger in the SSRI-exposed group (39.0 vs. 40.0 weeks). Additionally, the SSRI-exposed infants had a smaller head circumference (34.1 vs. 35.0 cm) and poorer Apgar scores at 1 minute (7.5 vs. 8.4).

Infants in the SSRI-exposed group also were more likely to have respiratory distress (30% vs. 3%) and jitteriness (39% vs. 3%).

"These are all things that have been previously documented, so basically, these kids are behaving the way that we expect from previous studies," commented Dr. Lim.

When it came to fetal right pulmonary artery parameters, there were no significant differences between SSRI-exposed and SSRI-nonexposed groups, or between morning and afternoon within the exposed group, in terms of pulsatility index, resistance index (a measure of blood flow impedance in the artery), peak systolic velocity, diameter, area, and flow.

However, within the SSRI-exposed group, fetal right pulmonary artery flow was higher for infants who experienced respiratory distress in the neonatal period than for those who did not, with a value of approximately 280 mL/min vs. 175 mL/min (P = .03).

Dr. Lim reported no relevant financial disclosures.

VANCOUVER, B.C. – The impact of selective serotonin reuptake inhibitors on fetal pulmonary vascular physiology may boil down to genetics, study results suggest.

In a study of 55 pregnant women who were near term, a variety of right pulmonary artery measures (such as flow and impedance) did not differ significantly between fetuses of women who had been taking SSRIs since conception and those of women who had not. There was also no measurable effect of acute exposure to SSRIs.

However, within the SSRI-exposed group only, fetal right pulmonary artery flow was about 40% higher for infants who experienced respiratory distress in the neonatal period than for their counterparts who did not.

"So there is something different about this particular group in terms of the fact that they developed respiratory distress," commented lead investigator Dr. Kenneth Lim. "Maybe they respond to the SSRIs differently; maybe there is a genetic polymorphism that makes them more susceptible."

Regardless, this difference can be tapped to elucidate the effects of in utero exposure, he added. "It just sort of gives us an idea that maybe we need to look at that a little bit more closely in the next phase of our studies, to try to determine whether there is something going on in the pulmonary system of these babies."

Some 4% of pregnant women in British Columbia are taking SSRIs, according to Dr. Lim of the department of obstetrics and gynecology at the University of British Columbia in Vancouver. "In a province our size, that’s about 1,500-2,000 patients a year who are exposed to SSRIs," he noted at the annual meeting of the Society of Obstetricians and Gynaecologists of Canada.

Previous studies have determined that maternal use of this class of drugs has a variety of deleterious effects on the infant, including low birth weight, prematurity, and a type of withdrawal syndrome characterized by irritability and jitteriness.

"But interestingly, there is also a link with respiratory distress, which tends to be more like a TTN [transient tachypnea of the newborn]-type respiratory distress, and also, there have been case reports of primary pulmonary hypertension," he noted.

The pathogenesis of these pulmonary abnormalities is unclear. "We do know that serotonin itself is a very powerful vasoconstrictor, but it has differential effects in different tissues," Dr. Lim explained.

Preclinically, serotonin impairs lung fluid resorption, suggesting that SSRI-exposed infants may be unable to reabsorb lung fluid after birth; one SSRI has been found to increase arterial smooth muscle cell proliferation.

Pregnant women were eligible for the study if their fetus did not have any anomalies, if they were not taking any illicit or prescription drugs (other than SSRIs), and if they did not have any serious medical conditions.

The investigators enrolled two groups. The nonexposed control group consisted of healthy women who were at low risk for complications and who had not taken SSRIs during pregnancy. The exposed group consisted of women with a mood disorder who had been taking SSRIs since the time of conception.

At a gestational age of about 36 weeks, the women underwent a morning ultrasound exam to assess fetal pulmonary vasculature. Those taking an SSRI then took their medication for the day. In the afternoon, all women had a second ultrasound.

This approach allowed assessment of the effects of both chronic SSRI exposure (by comparing exposed and nonexposed groups) and acute SSRI exposure (by comparing morning and afternoon measurements in the exposed group), Dr. Lim explained.

Results were based on 23 women taking SSRIs (predominantly fluoxetine) and 32 control women. They were 33 years old, on average. Only a single woman in each group smoked during pregnancy. Those in the SSRI group had higher scores for depression.

At delivery, the gestational age was significantly younger in the SSRI-exposed group (39.0 vs. 40.0 weeks). Additionally, the SSRI-exposed infants had a smaller head circumference (34.1 vs. 35.0 cm) and poorer Apgar scores at 1 minute (7.5 vs. 8.4).

Infants in the SSRI-exposed group also were more likely to have respiratory distress (30% vs. 3%) and jitteriness (39% vs. 3%).

"These are all things that have been previously documented, so basically, these kids are behaving the way that we expect from previous studies," commented Dr. Lim.

When it came to fetal right pulmonary artery parameters, there were no significant differences between SSRI-exposed and SSRI-nonexposed groups, or between morning and afternoon within the exposed group, in terms of pulsatility index, resistance index (a measure of blood flow impedance in the artery), peak systolic velocity, diameter, area, and flow.

However, within the SSRI-exposed group, fetal right pulmonary artery flow was higher for infants who experienced respiratory distress in the neonatal period than for those who did not, with a value of approximately 280 mL/min vs. 175 mL/min (P = .03).

Dr. Lim reported no relevant financial disclosures.

VANCOUVER, B.C. – The impact of selective serotonin reuptake inhibitors on fetal pulmonary vascular physiology may boil down to genetics, study results suggest.

In a study of 55 pregnant women who were near term, a variety of right pulmonary artery measures (such as flow and impedance) did not differ significantly between fetuses of women who had been taking SSRIs since conception and those of women who had not. There was also no measurable effect of acute exposure to SSRIs.

However, within the SSRI-exposed group only, fetal right pulmonary artery flow was about 40% higher for infants who experienced respiratory distress in the neonatal period than for their counterparts who did not.

"So there is something different about this particular group in terms of the fact that they developed respiratory distress," commented lead investigator Dr. Kenneth Lim. "Maybe they respond to the SSRIs differently; maybe there is a genetic polymorphism that makes them more susceptible."

Regardless, this difference can be tapped to elucidate the effects of in utero exposure, he added. "It just sort of gives us an idea that maybe we need to look at that a little bit more closely in the next phase of our studies, to try to determine whether there is something going on in the pulmonary system of these babies."

Some 4% of pregnant women in British Columbia are taking SSRIs, according to Dr. Lim of the department of obstetrics and gynecology at the University of British Columbia in Vancouver. "In a province our size, that’s about 1,500-2,000 patients a year who are exposed to SSRIs," he noted at the annual meeting of the Society of Obstetricians and Gynaecologists of Canada.

Previous studies have determined that maternal use of this class of drugs has a variety of deleterious effects on the infant, including low birth weight, prematurity, and a type of withdrawal syndrome characterized by irritability and jitteriness.

"But interestingly, there is also a link with respiratory distress, which tends to be more like a TTN [transient tachypnea of the newborn]-type respiratory distress, and also, there have been case reports of primary pulmonary hypertension," he noted.

The pathogenesis of these pulmonary abnormalities is unclear. "We do know that serotonin itself is a very powerful vasoconstrictor, but it has differential effects in different tissues," Dr. Lim explained.

Preclinically, serotonin impairs lung fluid resorption, suggesting that SSRI-exposed infants may be unable to reabsorb lung fluid after birth; one SSRI has been found to increase arterial smooth muscle cell proliferation.

Pregnant women were eligible for the study if their fetus did not have any anomalies, if they were not taking any illicit or prescription drugs (other than SSRIs), and if they did not have any serious medical conditions.

The investigators enrolled two groups. The nonexposed control group consisted of healthy women who were at low risk for complications and who had not taken SSRIs during pregnancy. The exposed group consisted of women with a mood disorder who had been taking SSRIs since the time of conception.

At a gestational age of about 36 weeks, the women underwent a morning ultrasound exam to assess fetal pulmonary vasculature. Those taking an SSRI then took their medication for the day. In the afternoon, all women had a second ultrasound.

This approach allowed assessment of the effects of both chronic SSRI exposure (by comparing exposed and nonexposed groups) and acute SSRI exposure (by comparing morning and afternoon measurements in the exposed group), Dr. Lim explained.

Results were based on 23 women taking SSRIs (predominantly fluoxetine) and 32 control women. They were 33 years old, on average. Only a single woman in each group smoked during pregnancy. Those in the SSRI group had higher scores for depression.

At delivery, the gestational age was significantly younger in the SSRI-exposed group (39.0 vs. 40.0 weeks). Additionally, the SSRI-exposed infants had a smaller head circumference (34.1 vs. 35.0 cm) and poorer Apgar scores at 1 minute (7.5 vs. 8.4).

Infants in the SSRI-exposed group also were more likely to have respiratory distress (30% vs. 3%) and jitteriness (39% vs. 3%).

"These are all things that have been previously documented, so basically, these kids are behaving the way that we expect from previous studies," commented Dr. Lim.

When it came to fetal right pulmonary artery parameters, there were no significant differences between SSRI-exposed and SSRI-nonexposed groups, or between morning and afternoon within the exposed group, in terms of pulsatility index, resistance index (a measure of blood flow impedance in the artery), peak systolic velocity, diameter, area, and flow.

However, within the SSRI-exposed group, fetal right pulmonary artery flow was higher for infants who experienced respiratory distress in the neonatal period than for those who did not, with a value of approximately 280 mL/min vs. 175 mL/min (P = .03).

Dr. Lim reported no relevant financial disclosures.

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.